Immunology of pregnancy

Question 1

What are some immunological problems needed to be solved in pregnancy

Answer 1

Fetal tissue is half foreign – has to be protected from rejection

Mother’s immune defence must be sufficient during pregnancy to ensure survival

Fetus often immunologically immature at birth – must have maternal antibodies to ensure survival

The maternal/fetal interface is central to overcoming these problems. This interface occurs at the placenta

Question 2

Where are the mother and baby cells in direct contact?

Answer 2

1.Syncytiotrophoblast layer covering the placenta is bathed in maternal blood
The syncytiotrophoblast is a multi-nucleated layer which arises from fused cytotrophoblasts. It forms a barrier and performs endocrine functions as well as gas and nutrient exchange from maternal blood.

2.Invading trophoblast come into contact with decidual immune cells
The extravillous trophoblast are differentiated fetal cells which invade into the maternal decidua to transform maternal spiral arteries.

3. Invading trophoblast come into contact with decidual blood vessels

Question 3

Where is the maternal foetal interface contact between?

Answer 3

syncytiotrophoblasts lining the chorionic villi and maternal blood in the intervillous space

invasive extravillous trophoblasts and maternal blood in the spiral arteries

invasive extravillous trophoblasts and infiltrated maternal immune cells in the decidua

Question 4

Which immune cells are present at the maternal-foetal interface

Answer 4

Decidua
>40% decidual cells are leukocytes in early pregnancy

  Of these, approximately 70% are NK cells (subpopulation of cytotoxic lymphocytes)
 function by cell killing or cytokine production

approximately 20% are macrophages

T and B cells make up the remaining 10%

Intervillous space and spiral arteries
same as maternal blood

Question 5

Describe decidual natural killer cells (dNK cells)

Answer 5

dNK cells are different to peripheral blood (pb)NK cells

Their pattern of receptor expression is unique and they are identified by CD56hiCD16lo

They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

Question 6

Describe macrophages in pregnancy (maternal immune cells)

Answer 6

Another immune cell found in the decidua is the macrophage: makes up about 20% of immune cells in the decidua so is the second most abundant immune cell

dMac have a different phenotype to peripheral blood monocytes

Broadly, macrophages may be:
M1: pro-inflammatory, secrete TNF-α, IL-6
M2: anti-inflammatory, secrete IL-10, VEGF

Decidual macrophages are more M2-like than M1-like

Question 7

How do trophoblasts evade the immune response

Answer 7

1) Physical separation of maternal and fetal tissues
Fetus separated from the mother by the fetal trophoblast cells
Fetal and maternal circulation is separated
Maternal cells cannot reach the fetus
But
In humans, IgG can cross into the fetal blood via a placental transport mechanism. Therefore IgG directed against fetal antigens could also be transferred
Why doesn’t this harm the baby?

2) Most fetal blood group and histocompatibility antigens are widely distributed on the fetal cells and tissues - IgG would be diluted out.
3) Many fetal antigens are also present as soluble forms in the fetal blood and amniotic fluid - IgG would be mopped up by free soluble antigen.

Antigenic immaturity of fetal tissues

Mother is immunologically inert

Question 8

Do foetal tissues have antigenic immaturity?

Answer 8

Histocompatibility antigens are targets for rejection
MHC haplotypes inherited from both parents and are co-dominantly expressed

Class Ia HLA-A, HLA-B, HLA-C
(classical) presenting antigens to CD8+ T cells
interacting with NK cells
highly polymorphic

Class Ib HLA-E, HLA-F, HLA-G
(non-classical) minimally polymorphic

Class II HLA-DP, HLA-DQ, HLA-DR
presenting antigen to CD4+ T cells

Question 9

What is the MHC expression on trophoblasts

Answer 9

Syncytiotrophoblasts lack both MHC Class I and II antigens

Extravillous trophoblasts lack Class II but express an unusual combination of MHC class I antigens –

HLA-C, HLA-E and HLA-G (non-classical)

Question 10

Is the mother immunologically inert?

Answer 10

Maternal blood in pregnancy is able to respond immunologically to the fetus and fetal cells are detectable in the maternal blood
BUT
Pre-sensitisation to paternal antigen does not prevent pregnancy

There is neither a generalised or specific depression of maternal immune responsiveness

The quality of the maternal immune response may be what differs

Question 11

What are some theories of immune evasion in the placenta?

Answer 11

Role for natural killer cells in the decidua

Selective local induction of programmed cell death in maternal immune cells

Alteration in the cytokine balance

Local indoleamine 2,3-dioxygenase synthesis

Complement regulatory proteins

Question 12

Decidual natural killer cells (and the difference compared to peripheral blood natural killer cells)

Answer 12

dNK cells are different to peripheral blood (pb)NK cells

Their pattern of receptor expression is unique and they are identified by CD56hiCD16lo

They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

Question 13

How does expression of HLA-C, -E and -G by EVT help immune evasion?

Answer 13

By binding to receptors on NK cells

NK cell receptors

Killer-cell immunoglobulin-like receptors (KIRs)
CD94/NKG2 receptors
Leukocyte immunoglobulin-like receptor (LILRs)

There are both inhibitory and activating members of these families of receptors

Question 14

Describe trophoblasts interacting with natural killer cells

Answer 14

Binding of HLA class I molecules to inhibitory NK cell receptors inhibits the cytotoxic action of the NK cell, therefore the trophoblast is not attacked

Inhibitory NK receptor- CD94/NKG2A, KIR2DL / S1, LILRB-1

Trophoblast- HLA C, E, G

Question 15

What is the experimental evidence for this

Answer 15

Inhibitory receptors are expressed at higher levels in uterine NK cells than peripheral blood NK cells

HLA-E has higher affinity for the inhibitory receptor than the activating receptor

More uNK cells found in women with a history of recurrent pregnancy loss

But
Trophoblast HLA molecules can also bind to activating NK cell receptors
may alter the NK cytokine repertoire
may contribute to how the trophoblast behaves

Question 16

What is the role of soluble HLA-G?

Answer 16

Soluble HLA-G can be released from trophoblasts

In vitro studies have shown that sHLA-G can induce apoptosis in maternal T cells

May be an additional way of protecting trophoblasts from attack

IVF: an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success

Question 17

Describe the need for selective local induction of programmed cell death in maternal immune cells

Answer 17

xperimental evidence that trophoblasts can induce programmed cell death (apoptosis) in maternal immune cells.

Apoptosis
Cell shrinks, nucleus reorganises, DNA fragments, membranes bleb and cell fragments into membrane bound apoptotic bodies.

Regulation of apoptosis depends on a balance between pro- and anti-apoptotic factors.

Mechanisms
Fas-Fas L
TRAIL-TRAIL R

Question 18

Describe the balance of Th1 and Th2 balance in pregnancy

Answer 18

T cells differentiate into Th1 or Th2 cells in response to signals given during antigen presentation

Th1 type reaction in placenta mainly generates inflammatory responses, activates T cells and NK cells and is correlated with miscarriages.
eg IFNg, IL-2

Th2 type reaction generates non-inflammatory reactions that are consistent with the survival of the fetus.
eg IL-4, IL-6, IL-10, IL-13

Trophoblasts may be producing
cytokines and hormones that
promote a Th2 balance.

Question 19

Maternal T cells

Answer 19

Skewing the nature of the T cell response to active tolerance rather than active rejection is important

T helpers – Th1, Th2, Th17, Treg

Sufficient Tregs needed in the endometrium for implantation and pregnancy
Tregs CD4+CD25+ – anti-inflammatory, immune suppressive
Act on other immune cells, produce suppressive cytokines such as TGFb and IL10

How is this regulated?
Appropriate cytokine balance
Correct phenotype of endometrial leukocytes to allow Treg activation
Stabilisation of Treg phenotype by estrogen and progesterone
Priming of Tregs by male partner seminal fluid-stimulates expansion of endometrial Treg population.

Question 20

Describe Indoleamine 2,3- dioxygenase

Answer 20

Enzyme that catabolises tryptophan
Synthesised and secreted by syncytiotrophoblasts
Shown to be essential for successful pregnancy

IDO may break down tryptophan in maternal T cells in the decidua

This can reduce or inhibit immune responses

Question 21

Describe the expression of complementary regulatory proteins

Answer 21

In normal pregnancies, excessive complement activation is prevented by complement regulatory proteins that are highly expressed on trophoblast membranes(MCP, DAF, and CD59)

This prevents cell lysis

CD46 – MCP – membrane co-factor protein
CD55 – DAF – decay accelerating factor
CD59 - MAC-IP- MAC inhibitory protein

Question 22

Is thereany immunological basis for disorders of pregnancy?

Answer 22

This is a controversial and heavily-researched area

Some incidences of pre-eclampsia and miscarriage may have a basis in maternal-fetal immunological mismatch

Question 23

Pre-eclampsia

Answer 23

PE lower risk with different partner for 2nd pregnancy
Donor egg pregnancies at higher risk (non-self)
Prolonged exposure to paternal semen may lower PE risk

dNK receptors may be Type A or B, and trophoblast receptors may be type C1 or C2

If the match is KIR-A and HLA-C2, pre-eclampsia risk is increased

This may be because this interaction leads to less cytokine production which helps the trophoblast invade

Question 24

Are immune cells different in high resistance and low resistance pregnancies?

Answer 24

dNK cells Promote trophoblast invasion Fail to promote trophoblast invasion
dNK cells Promote spiral artery remodelling Fail to promote spiral artery remodelling
dNK cells Differ in cell surface receptors
dNK cells Differ in cytokine secretion
dMacrophage Do not induce trophoblast apoptosis Induce trophoblast apoptosis